Upper aerodigestive tract cancers, like lung cancer, are major contributors to cancer morbidity and mortality. Although smoking and alcohol consumption are the major risk factors for these cancers, the fact that only a fraction of the exposed individuals develop cancer suggests that host-specific factors also influence the likelihood of cancer development. Understanding of susceptibility factors could help to identify high risk individuals for cancer intervention. The variation in susceptibility to tobacco carcinogens may be due to genetically determined variations in carcinogen activation and detoxification as well as DNA repair. Most chemical carcinogens require metabolic activation to form DNA reactive species which could covalently bind to DNA resulting DNA adduct formation. If adducts are not repaired before DNA replication, they could cause gene mutations. Therefore, DNA adduct formation is a key event in early stages of chemical carcinogenesis. DNA adducts represent the sum of carcinogen metabolism and DNA repair. The formation and removal of DNA adducts after carcinogen exposure may reflect individual susceptibility to carcinogen-induced cancer. This hypothesis has been tested in a pilot study involving 21 lung cancer cases and 41 healthy controls by using an induced adduct assay. Peripheral lymphocytes from these study subjects were treated with a tobacco carcinogen, benzo[a]pyrene diol epoxide (BPDE) and DNA adducts were measured by 32P-postlabeling. The level of BPDE-induced DNA adducts was found to be a significant and independent risk factor for lung cancer (odds ratio 6.4). While these initial findings are being expanded in a larger scale lung cancer study, the purpose of the current project is to demonstrate whether this assay can be applied to other smoking-related cancers. In an ongoing NIH-funded molecular epidemiology study of 100 head and neck cancer cases and 100 cancer- free controls, the expression levels of 5 DNA repair genes (XPCC, ERCC1, XRCC1, hMLH1, and hMSH-2) in lymphocytes are being measured. We propose to use blood samples and epidemiologic data collected from this study to test our hypotheses that the levels of BPDE-induced DNA adducts are associated with risk of head and neck cancer and the adduct levels are inversely correlated with the expression level of DNA repair genes. DNA adducts will be measured in BPDE-treated peripheral lymphocytes of 100 head and neck cancer cases and 100 cancer-free controls by 32P-postlabeling. The levels of adducts will be evaluated in association with risk of development of head and neck cancers controlled for other known risk factors and in relation to the expression level of DNA repair genes. This study may provide a new method of identifying high-risk individuals for smoking-related human cancers and may provide information on the mechanism involved in carcinogen-induced tumorigenesis.